
 efferocytosis is a carefully orchestrated process by which phagocytes are recruited to sites of cell death , recognize and engulf dying cells , and clear them in an  immunologically silent ' manner.dying cells have an active role in their own clearance ; via the production of  find - me ' signals to attract phagocytes and exposure of  eat - me ' signals that engage phagocytic receptors to facilitate engulfment.defects in the efferocytosis machinery are associated with inflammation and autoimmune disorders , such as systemic lupus erythematosus ( sle).microtubule - associated protein 1a/1b - light chain 3 ( lc3)-associated phagocytosis ( lap ) is required for the effective clearance of dying cells . 
 
efferocytosis is a carefully orchestrated process by which phagocytes are recruited to sites of cell death , recognize and engulf dying cells , and clear them in an  immunologically silent ' manner .
dying cells have an active role in their own clearance ; via the production of  find - me ' signals to attract phagocytes and exposure of  eat - me ' signals that engage phagocytic receptors to facilitate engulfment .
defects in the efferocytosis machinery are associated with inflammation and autoimmune disorders , such as systemic lupus erythematosus ( sle ) .
microtubule - associated protein 1a/1b - light chain 3 ( lc3)-associated phagocytosis ( lap ) is required for the effective clearance of dying cells .

 given the variety of  find - me ' and  eat - me ' signals , as well as their cognate receptors , how do these signals coordinate for effective efferocytosis?how does lap promote the anti - inflammatory response to dying cells , and what role does macrophage metabolism have?do defects in lap contribute to inflammatory or autoimmune pathogenesis?what role does lap have in oncogenesis ?
what role does lap have in tumor - associated macrophages ? 
  given the variety of  find - me ' and  eat - me ' signals , as well as their cognate receptors , how do these signals coordinate for effective efferocytosis ? how does lap promote the anti - inflammatory response to dying cells , and what role does macrophage metabolism have ?
even from our earliest developmental stages , the process of generating and maintaining a multicellular , functional organism is characterized by the creation and unceremonious destruction of billions of cells . programmed cell death , such as apoptosis , necroptosis , or pyroptosis ,
are active mechanisms designed to sculpt , control , and aid the body in its development and survival .
much of our knowledge on the role of apoptosis in development comes from the study of caenorhabditis elegans , wherein the first wave of cell death occurs ~4  h after fertilization , and of the 1090 cells that are generated , 131 of them are destined for death . in mammalian embryos ,
it is now well understood that proper apoptosis is fundamental for the proper development of the organism , as deficiencies in mediators of apoptosis result in embryonic lethality or animals with severe malformations .
conversely , other forms of cell death , such as necroptosis and pyroptosis , are not required during development , as evidenced by the normal development of mice deficient for receptor interacting protein kinase3 or caspase-1/11 , respectively . once formed , the organism 's relationship with cell death is far from over .
cellular turnover is a constant , genetically programmed process in the adult animal , and removal of these unwanted and unneeded cellular corpses is vital to prevent unwanted inflammation and immune activation .
although damage can certainly cause unwanted cellular death , most cellular death is an active process , and perturbations in the cell death programs can promote cell accumulation , autoimmunity , oncogenesis , attrition , and/or degeneration . within tissues , professional , non - professional , and specialized phagocytes
the best - characterized population of professional phagocytes , macrophages , is composed of tissue - specific , differentiated subsets of resident macrophages that clear dying cells and debris .
for example , kupffer cells in the liver clear aged red blood cells ; aveolar macrophages of the lung clear apoptotic airway epithelial cells , and microglia in the central nervous system clear dying neurons .
other types of resident cells , such as epithelial cells and fibroblasts , have been termed non - professional phagocytes ; though this designation may be a misnomer as these cells have a major role when professional phagocytes are rare , such as in the mammary gland or intestinal epithelium .
in addition , airway epithelial cells are critical for the clearance of apoptotic airway epithelial cells , and epithelial cell - specific deletion of rac1 results in increased allergen - induced airway inflammation . still other types of tissue - specific , multifunctional cells exist as specialized phagocytes . in the testes , sertoli cells are responsible for clearing apoptotic germ cells that arise during spermatogenesis . in the eye ,
retinal pigment epithelial ( rpe ) cells are critical for the homeostatic , daily removal of the photoreceptor outer segments ( poss ) , and the generation of 11-cis - retinal for the visual cycle .
defects in rpe cell - mediated removal of outer segments ( or processing of outer segments via lap , discuss below ) can lead to a predisposition to conditions , such as age - related macular degeneration or retinitis pigmentosa . like the death process itself
, the innate immune system has tolerance systems in place to manage these morbid , yet necessary events .
although the generation and subsequent destruction of these cells is necessary for normal cellular homeostasis , wound healing , and immune responses in the adult organism , the ruin left in its wake would be catastrophic if not for the efficient work of the phagocytic system . despite the constant , homeostatic turnover of cells , as well as cell death induced by stress , damage , or infection , it is rare to observe apoptotic cells under normal physiological conditions . considering the average one million adult human cells that undergo apoptosis every second
, one can appreciate the magnitude of the job facing phagocytes moreover , as this is a reoccurring and normal event in the lifespan of an organism , this process of dead cell clearance must occur in a quiescent manner , so as to not inappropriately alert the immune system .
we now appreciate the critical role that efferocytosis has on modulating immunity , as well as the impact that different types of cell death have on the immune response . in this review
, we discuss the process of efferocytosis , chemoattraction of phagocytes , recognition of dying cells , engulfment of cellular corpses , and the processing of engulfed cellular cargo , specifically the role of lap in clearance of dying cells and control of inflammation .
as the focus of this review is the aftermath of cell death , we have summarized the four most well - defined modes of cell death ( apoptosis , necrosis , necroptosis , and pyroptosis ) in table 1 , as the roles and mechanisms of cell death have been studied and reviewed extensively .
efferocytosis is not merely a passive event , but a carefully orchestrated process designed to efficiently eliminate cellular corpses and limit exposure to their potentially damaging components , with the goal being immunological tolerance .
efferocytosis can be generally categorized into 4 steps : 1 ) the release of  find - me ' signals by dying cells to recruit phagocytes , 2 ) phagocyte recognition and engagement of  eat - me ' signals on dying cells , 3 ) the engulfment of the cellular corpse , and 4 ) the processing , degradation , and immune response to the engulfed corpse .
we now recognize that defects in any of these four steps can contribute to unwanted inflammation and autoimmune disorders , such as systemic lupus erythematosus ( table 2 ) .
as phagocytes are often not proximal to sites of cell death or even reside in the tissues they must survey , dying cells must 
recruitment of phagocytes to sites of cell death in c. elegans occurs before the completion of apoptosis , indicating that one of the first acts of a dying cell is to prepare for its own elimination . during this process ,
apoptotic cells release  find - me ' signals , distinct molecules that establish a chemotactic gradient to attract phagocytic cells .
nucleotides , such as atp , are released in a caspase - dependent manner via activation of pannexin-1 channels and are perhaps the most well - defined  find - me ' signals .
these nucleotides are detected by phagocytes via purinergic receptors , like p2y2 , and disruption of the nucleotide / p2y2 interaction results in an accumulation of dying cells in vivo .
apoptotic cells also release the membrane - associated molecule fractalkine ( or cx3cl1 ) , which is sensed by cx3cr1 and mediates the migration of macrophages to the dying cells .
mice deficient for cx3cr1 , however , do not display a defect in apoptotic cell clearance , suggesting that multiple factors are required to recruit effectively phagocytes .
lysophosphatidylcholine is generated and released via caspase-3-dependent activation of phospholipase a , and is sensed by the g - protein - coupled receptor g2a .
sphingosine-1-phosphate ( s1p ) , also a lipid  find - me ' signal , is released by dying cells and sensed by multiple g - protein - coupled receptors s1p - r1 - 5 .
there are significant caveats to the ability of  find - me ' signals to efficiently act as chemoattractants in physiologically scenarios .
the idea of an apoptotic cell 's purposeful release of a  find - me ' signal to actively recruit phagocytes is undermined by the relatively low level of signal released by apoptotic cells compared with necrotic cells . 
find - me ' signals are often released in an active , caspase - dependent manner , yet these molecules are also released ( and in greater quantities ) during other forms of cell death , such as necrosis or necroptosis .
in addition , these released nucleotides must also survive degradation by extracellular nucleotidases , indicating that they most likely act in a short - range capacity . similarly , 
find - me ' signals of lipid origin are present ubiquitously in the circulation at a concentration higher than that released by apoptotic cells .
find - me ' signals , which can be recognized by a wide variety of cells , specifically recruit phagocytes , the majority of which are macrophages , are unknown . the counteractive effect of  keep out ' signals has been proposed to aid in the coordinated recruitment of phagocytes .
for example , lactoferrin , a glycoprotein released by apoptotic cells , has been shown to actively exclude neutrophils and eosinophils from sites of cell death . further complicating
the matter is the dual role that  find - me ' signals can have , as danger - associated molecular patterns ( damps ) or as activating factors to prime phagocytes .
cell death does not occur in a vacuum ; sites of cell death are a conglomeration of dying cells , healthy cells , and immune cells .
the phagocyte must distinguish living cells from dying cells in order to maintain homeostasis , promote proper development , and prevent unwanted inflammation .
just as dying cells must recruit phagocytes , they must also transform themselves into targets for engulfment , displaying distinct signals that differentiate them from viable cells .
the extracellularly exposed lipid , phosphatidylserine ( ptdser ) , is the most well - characterized  eat - me ' signal and an essential factor in effective efferocytosis .
normally confined to the inner leaflet of the plasma membrane lipid bilayer of living cells ( and in a relatively minor amount ) , ptdser is actively and rapidly externalized in a caspase - dependent manner during apoptosis .
caspase 3-mediated cleavage of the scramblase xkr8 facilitates exposure of ptdser during apoptosis , an event normally reversed by the activity of the flippase atp11c , which is inactivated by caspase-3 cleavage .
extracellularly exposed ptdser is recognized by multiple , bona fide membrane receptors , such as t - cell immunoglobulin mucin receptor 4 ( tim4 ) , brain - specific angiogenesis inhibitor 1 ( bai1 ) , and stabilin-2 , and bridging molecules , such as milk fat globule - egf factor 8 ( mfg - e8 ) and gas6 , that recognize ptdser and then engage phagocytic cell surface receptors such as integrin v3 , v5 , or tryo3-axl - mer ( tam ) receptors for engulfment .
eat - me ' signals have also been identified , which are likely to have a  tethering ' function , facilitating the above events .
icam3 can bind to membrane - associated cd14 , and externalized calreticulin bound to complement c1q can engage cd91 ( or lrp1 ) .
oxidized ldl - like moieties and glycosylated surface proteins can serve as  eat - me ' signals , binding to scavenger receptors and lectins , respectively ( figure 1b ) .
similar to the  find - me'/'keep out ' signal paradigm , there is evidence of a negative signal to discourage phagocytosis .
although ptdser is considered a hallmark of cell death , forced ptdser exposure or physiologically normal exposure on activated , living cells does not mediate recognition or engulfment .
thus , the simultaneous presence of  do n't eat - me ' signals , such as cd31 , cd47 , and cd61 , on viable cells , may negatively regulate phagocytosis , indicating to the phagocyte that despite the extracellular ptdser , this cell is not intended for clearance .
therefore , a coordinated effort between the dying cell and the phagocyte must exist to facilitate efferocytosis .
although the majority of work on  find - me ' and  eat - me ' signals stems from apoptotic cells , these signals also function during other types of cell death , such as necroptosis and pyroptosis .
as previously mentioned ,  find - me ' signals , such as atp , are released ( and in greater quantities ) during necrosis , necroptosis , and pyropotosis .
similarly , necrotic and pyroptotic cells also stain positive for annexin v , although in these cases , externalized ptdser can be attributed to rupture of the plasma membrane rather than an active exposure process .
these dead cells can still be recognized and engaged by ptdser receptors ; however , owing to the lytic nature of their demise , damps have already been released into the milieu and can activate inflammatory programs .
therefore , although apoptotic cells actively coordinate their own clearance , necrotic and pyroptotic cells passively utilize these systems as well . the tissue specificity of ptdser receptors may help to explain why multiple receptors are required for efficient efferocytosis .
stabilin-2 is highly expressed in endothelial cells within atherosclerotic plaques , although defects in bai1 , highly expressed in glial and neuronal cells , are associated with neurodegenerative disorders . despite a common ligand and a common goal of engulfment ,
once engaged by ptdser - bound integrins , bridging molecules , such as v3 or tam , associates with the adapter proteins elmo1 and dock180 ( via crkii ) at the site of phagoytosis .
the ptdser receptor bai1 also requires the activity of the dock180/elmo1 complex for engulfment , but bai1 is able to recruit the complex independently .
stabilin-2 and cd91/lrp , however , require the activity of the adapter protein , gulp , to facilitate phagocytosis .
one of the most well - known ptdser receptors , tim4 , contains a very short cytoplasmic region and currently its signaling components are unknown . dying cell engulfment involves active membrane ruffling by a process similar to macropinocytosis .
engagement of ptdser receptors results in cytoskeletal reorganization to facilitate phagocytosis , which is mediated by the rho family of small gtpases , including members rhoa , rock , rac , rab5 , and cdc42 .
these gtpases cycle between the resting , inactive gdp - bound state and the active gtp - bound state , mediated by specific guanine - nucleotide - exchange factors ( gefs ) , such as the bipartite gef formed by dock180 and elmo1 . ultimately , signaling during efferocytosis converges on the activation of evolutionarily conserved rac1 , acting at the phagocytic cup to promote actin polymerization and cytoskeletal rearrangement via the scar / wave complex .
similarly , cdc42 has been linked to the engulfment of apoptotic cells , although its precise role is unclear .
once encased within the phagocyte , however , the dying cell is now capable of exerting its effect on critical downstream immunological and metabolic pathways .
the mechanisms by which phagocytes handle the burden of processing an engulfed cellular corpse are currently of great interest . not only must a phagocyte interpret its ingested cargo in an immunologically tolerant manner
, it must also contend with the excess lipid , cholesterol , and protein that an entire engulfed cell brings .
acidic proteases and nucleases in mature phagolysosomal compartments degrade dying cells into their basic cellular components , including fats , sterols , peptides , and nucleotides .
for example , dnase ii , a lysosomal enzyme , is required for the degradation of dna , and dnase ii deficiency results in an accumulation of undigested dna fragments within phagocytic cells , capable of activating intracellular nucleic acid sensors .
the two ancient systems of phagocytosis and autophagy represent two modes of nutrient acquisition , during abundance and scarcity , respectively .
these two evolutionarily conserved pathways converge , however , during the engulfment of pathogens or dead cells .
lap is a process that marries the processes of phagocytosis and autophagy into a fundamentally new concept , allowing us to reinterpret the impact of the autophagy machinery on innate host defense mechanisms ( table 3 ) .
lap is triggered when an extracellular particle , such as a pathogen , immune complex , or dead cell , is sensed by an extracellular receptor , including toll - like receptor1/2 ( tlr1/2 ) , tlr2/6 , tlr4 , fcr , and tim4 , and phagocytosed
. this engulfment recruits some , but not all , members of the autophagy machinery to the cargo - containing vesicle .
it is the activity of these autophagic players that facilitates the rapid processing of the cargo via fusion with the lysosomal pathway , which can have a critical role in the degradation of engulfed cargo , as well as modulate the resulting immune response . despite sharing common molecular machinery ,
there currently exist several distinctions that differentiate lap from canonical autophagy ( figure 2 ) .
originally , lap and autophagy were distinguished by the structure of the lc3-decorated phagosome ( or laposome ) and the rapidity with which lap occurs .
em analysis revealed that lap results in single - membrane structures , as opposed to the double - membrane autophagosomes surrounding autophagic cargo .
whereas lc3-decorated autophagosomes can take hours to form , lc3-ii can be detected on laposomes in as few as 10  min after phagocytosis , and phosphatidylinositol 3-phosphate ( pi(3)p ) activity can be seen at the laposome within minutes after phagocytosis .
recent studies have elucidated the molecular mechanisms governing lap . although a majority of the core autophagy components are required for lap , there exist some critical differences that can distinguish the two processes . under basal conditions , mtor inhibits the pre - initiation complex , comprised of fip200 , autophagy - related gene13 ( atg13 ) , and ulk1/2 , and hence autophagy .
furthermore , canonical autophagy requires the ulk1-dependent release of a beclin1-activating cofactor , ambra1 , from the dynein motor complex , and the function of wipi2 , whereas lap does not
. both lap and canonical autophagy require the class iii pi3k complex , which contains the core components beclin1 , vps34 , and vps15 .
atg14 and uvrag are mutually exclusive in their association with the class iii pi3k complex during autophagy , and silencing of either atg14 or uvrag inhibits canonical autophagy .
lap , on the other hand , only requires the activity of the uvrag - containing class iii pi3k complex , whereas atg14 is dispensible .
rubicon ( run domain protein as beclin 1 interacting and cysteine - rich containing ) is a protein that associates constitutively with the uvrag - containing class iii pi3k complex .
rubicon is a negative regulator of autophagy ( via its inhibition of vps34 or by blocking gtpase rab7 activation ) , and silencing of rubicon results in an increase in the number of autophagosomes . during lap
, rubicon is uniquely associated with laposomes ( but not conventional phagosomes ) , and rubicon - deficient cells are completely defective in lap .
thus , rubicon is a molecule that is uniquely required for lap , but dispensable for canonical autophagy .
first , rubicon promotes the association of the active class iii pi3k complex with the laposome , thereby aiding in the localization of vps34-mediated pi(3)p at the laposome . in both canonical autophagy and lap , pi(3)p is required for the recruitment of the downstream ubiquitin - like conjugation systems , the atg5 - 12 and lc3-pe conjugation systems . in lap ,
rubicon stabilizes nox2 , the predominant nadph oxidase in phagocytes , by interacting with its p22 subunit via its serine - rich domain ( aa 567625 ) , a domain separate from the ccd domain ( aa 515550 ) responsible for its interaction with beclin1 and the run domain ( aa 49180 ) responsible for its interaction with vps34 . moreover , pi(3)p binds and stabilizes the p40 subunit of nox2 .
collectively , rubicon promotes the association of the active class iii pi3k complex with the laposome and the production of pi(3)p .
rubicon and pi(3)p stabilize the active nox2 complex to promote optimal reactive oxygen species ( ros ) production , which is also required for successful lap .
indeed , nox2-deficeint cells fail to undergo lap and scavenging of ros by antioxidants , such as resveratrol , tiron , or alpha - tocopherol is also an effective way to inhibit lap .
there is mounting evidence that lap is a critical regulator of inflammation in vivo and under physiologically relevant conditions . not only is lap critical for the degradation of engulfed organisms , such as intraphagosomal yeast or aspergillus fumigatus , but lap can have a profound effect on the immune response to the engulfed material .
upon intranasal challenge with a. fumigatus , a tlr2 ligand , lap - deficient animals fail to efficiently clear the pathogen and display increased levels of pro - inflammatory cytokines both locally ( lung ) and systemically ( serum ) .
thus , many of the autophagic defects associated with control of pathogens could actually be defects in lap .
lap can also be triggered in specialized phagocytes , such as the rpe . on a daily basis and
regulated by circadian rhythm , rpe cells phagocytose and digest shed poss , a process crucial for supplying nutrients and o2 to the retina and the metabolism of vitamin a for the visual cycle .
what is known is the requirement for lap in the proper processing of pos and promotion of the visual cycle , a series of biochemical reactions within the rpe and retina that ultimately results in the production of the chromophore 11-cis - retinal ( ral ) necessary for the phototransduction signaling cascade .
rpe cells deficient for lap ( atg5 , beclin1 ) , but not canonical autophagy ( ulk1 , fip200 , atg13 ) displayed defective pos degradation , diminished production of 11-cis - retinal , and decreased visual function with age .
thus , lap functions to support chromophore regeneration through the efficient processing of pos by the rpe . lap is also required for establishing specific signaling compartment and is a critical regulator of the type i interferon response in some cases . in plasmacytoid dendritic cells ,
lap is induced by engagement of the fcr by immune complexes ( ic ) , complexes of self - antigen ( such as dna ) and autoantibodies commonly found in patients with sle . in cells deficient for lap , failure to lipidate lc3 on the dna - ic - containing laposome results in a failure to acquire a late - endolysosomal phenotype .
subsequently , these lap - deficient cells fail to form the specialized interferon regulatory factor 7 ( irf7)-signaling compartment required for tlr9-mediated activation of irf7 , and therefore fail to produce ifn-. this suggests that lap could affect the functional immune response elicited by autoantigens and have an important role in autoimmunity . unwanted inflammation and autoimmunity
it is the responsibility of the phagocytes to first clear the dying cell from circulation and then instigate an anti - inflammatory response .
phagocytes that have engulfed apoptotic cells have been shown to secrete anti - inflammatory cytokines , such as tgf and interleukin-10 ( il-10 ) , whereas actively suppressing pro - inflammatory cytokines , such as tumor necrosis factor , il-1 , and il-12 .
lap is triggered during efferocytosis , and apoptotic , necrotic , and necroptotic cells can engage the ps receptor , tim4 , resulting in a recruitment of the lap machinery to the dead - cell - containing , single - membrane laposome .
lap - deficient macrophages fail to recruit lc3 to the laposome , leading to a failure in phagosomal acidification and subsequent corpse degradation . whereas the paradigm of efferocytosis is  immunologically silent '
, lap - deficient macrophages produce markedly increased levels of il-1 and il-6 when fed dying cells , yet produce significantly less anti - inflammatory cytokines , such as il-10 , upon such engulfment .
lap is engaged by a variety of receptors and is critical for directing a variety of different immune response , including preventing an unwanted inflammatory response and promoting the formation of the interferon signaling compartment .
although these functions may appear contradictory , it suggests that the fundamental role of lap is to shape the appropriate response , and absence of this pathway seems to result in aberrant inflammation and pathogen control .
how the lap pathway modulates the immune response to apoptotic cells remains to be elucidated , though clues may lie in the mechanisms by which the phagocyte handles the metabolic stress of doubling its content of cellular components .
the sensing of one such component , cholesterol , can have a significant effect on the phagocyte 's response to engulfed dead cells and their increase in basal cholesterol efflux activity .
members of the peroxisome proliferator - activated receptor / ( ppar/ ) and liver x receptor ( lxr ) families , both important regulators of cellular lipid homeostasis , are activated during efferocytosis , and results in a positive feedback signal wherein the phagocytic receptors , such as members of the tam family , are upregulated . furthermore , cholesterol efflux machinery , such as 12-transmembrane protein abca1 ( atp - binding cassette sub - family a , member 1 ) , is upregulated to accommodate the increase in cholesterol load .
the non - immunogenic nature of efferocytosis of apoptotic cells is one of its key characteristics , and cholesterol homeostasis has a critical role in establishing this tolerance .
ppar/ are central players in the polarization of anti - inflammatory (  m2 ' ) macrophages , and agonizts for both ppar and lxr have been shown to inhibit inflammatory responses .
the dual functions of ppars and lxrs in both lipid apoptotic cell clearance and lipid homeostasis suggest the interconnectedness between efferocytosis and metabolism . despite all types of dying cells providing excess cholesterol for the engulfing cells , uptake of necrotic cells does not induce enhanced cholesterol efflux in the phagocytes , suggesting that engagement of ligands on apoptotic cells , not extra cholesterol ,
studies have shown that mere co - culture of macrophages with ptdser liposomes can induce the cholesterol efflux , anti - inflammatory cytokine production , and suppression of pro - inflammatory genes .
these data suggest that metabolic sensors , in conjunction with engagement of  eat - me ' signals , such as ptdser , contribute to the immunological tolerance associated with efferocytosis .
defects at multiple points in the efferocytosis pathway have been reported to result in unchecked inflammation or autoimmunity , and understanding the mechanisms by which dying cells are effectively cleared can pave the way for therapies that target these processes .
although many studies have examined inflammatory disorders in the context of defective attraction , recognition , and physical engulfment of dead cells , we now recognize that aberrant processing of dead cells , potentially via deviations in lap , can also result in inflammation .
although systemic disorders , such as sle , have been long linked to defects in dying cell clearance and the autophagy machinery , more definitive roles for these pathways in  localized ' inflammatory diseases , such as ulcerative colitis , atherosclerosis , neurodegeneration , and rheumatoid arthritis should be described . moreover
, the intricate link between inflammation and cancer raises the question of what the role of efferocytosis is during tumor development , metastasis , and chemotherapy - mediated tumor clearance .
although clearance of dying cells is a common occurrence in healthy and diseased cells , recent studies describe the process of entosis , wherein living cells are engulfed by phagocytes .
although some entotic cells can escape from their engulfment unscathed , most are targeted for destruction by lap .
the mechanisms by which entosis occurs , and its similarity to efferocytosis , implies that the burden that lays before the phagocytic system is a daunting one .
 phagocytic cells of the immune system must constantly survey for , recognize , and efficiently clear the billions of cellular corpses that arise as a result of development , stress , infection , or normal homeostasis . 
 this process , termed efferocytosis , is critical for the prevention of autoimmune and inflammatory disorders , and persistence of dead cells in tissue is characteristic of many human autoimmune diseases , notably systemic lupus erythematosus 
 . the most notable characteristic of the efferocytosis of apoptotic cells is its  immunologically silent ' response . 
 although the mechanisms by which phagocytes facilitate engulfment of dead cells has been a well - studied area , the pathways that coordinate to process the ingested corpse and direct the subsequent immune response is an area of growing interest . 
 the recently described pathway of lc3 ( microtubule - associated protein 1a/1b - light chain 3)-associated phagocytosis ( lap ) has shed some light on this issue . 
 lap is triggered when an extracellular particle , such as a dead cell , engages an extracellular receptor during phagocytosis , induces the translocation of autophagy machinery , and ultimately lc3 to the cargo - containing phagosome , termed the laposome . in this review 
 , we will examine efferocytosis and the impact of lap on efferocytosis , allowing us to reimagine the impact of the autophagy machinery on innate host defense mechanisms . 
Facts
Open Questions
An Introduction: Can I Interest You in Any Appetizers?
The Mechanisms of Efferocytosis: Would You Like to Hear the Specials?
Degradation After Phagocytosis: Did You Save Room for Dessert?
Conclusions: Check Please!