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SummaryNatural antibodies (NAbs) are circulating polyreactive immunoglobulins that bind endogenous and exogenous antigens. Here, we investigated the role of NAbs in driving the clearance of necrotic cell debris from injury sites. Using mouse models of liver injury, we observed that IgM and IgG NAbs opsonize necrotic debrisin vivoby recognizing common self-molecules such as histones, actin, phosphoinositides and cardiolipin, but not phosphatidylserine. Importantly, mice lacking NAbs presented impaired recovery from liver injury, which was correlated to sustained presence of necrotic debris in the tissue, prolonged inflammation and reduced hepatocellular proliferation. Mechanistically, necrotic debris phagocytosis was dependent on NAbsin vitroandin vivo, and restitution with total immunoglobulins rescued the defective recovery from liver injury in immunodeficient mice. In summary, we showed that NAbs opsonize necrotic cell debris and act as “eat-me” signals for engulfment through FcγRs and CD11b, driving the recovery from tissue injury.HighlightsNatural antibodies opsonize exposed self-antigens upon necrotic cell death.The phagocytosis of necrotic cell debris requires natural antibodies, FcγRs and CD11b.Natural antibodies drive cellular proliferation and tissue regeneration after liver injury.Treatment with natural antibodies improves the recovery from liver injury in both immunodeficient and immunocompetent mice.Graphical abstract

Leafcutter ants farm a fungal cultivar (Leucoagaricus gongylophorus) that converts inedible vegetation into food that sustains colonies with up to millions of workers. Analogous to edible fruits of crops domesticated by humans, L. gongylophorus has evolved specialized nutritional rewards—swollen hyphal cells called gongylidia that package metabolites ingested by ant farmers. Yet, little is known about how gongylidia form, and thus how fungal physiology and ant provisioning interact to farming performance. We explored the mechanisms governing gongylidium formation using microscopy imaging of ant-cultivated fungus and controlled in vitro experiments with the cultivar grown in isolation from ant farmers. First, L. gongylophorus is polykaryotic (up to 17 haploid nuclei/cell) and our results suggest intracellular nucleus distributions govern gongylidium morphology with their absence in expanding edges arresting apical growth and their presence mediating complex branching patterns. Second, nanoscale imaging (SEM, TEM) shows that the cultivar recycles its own cellular material (e.g. cytosol, mitochondria) through a process called ‘autophagy’ and stores the resulting metabolites in gongylidia. This autophagic pathway is further supported by gongylidium suppression when isolated fungal cultures are grown on media with autophagy inhibitors, and differential transcript expression (RNA-seq) analyses showing upregulation of multiple autophagy genes in gongylidia. We hypothesize that autophagic nutritional reward production is the ultimate cultivar service and reflects a higher-level organismality adaptation enabled by strict symmetric lifetime commitment between ant farmers and their fungal crop.

Clearance of cellular debris is required to maintain the homeostasis of multicellular organisms. It is intrinsic to processes such as tissue growth and remodeling, regeneration and resolution of injury and inflammation. Most of the removal of effete and damaged cells is performed by macrophages and neutrophils through phagocytosis, a complex phenomenon involving ingestion and degradation of the disposable particles. The study of the clearance of cellular debris has been strongly biased toward the removal of apoptotic bodies; as a result, the mechanisms underlying the removal of necrotic cells have remained relatively unexplored. Here, we will review the incipient but growing knowledge of the phagocytosis of necrotic debris, from their recognition and engagement to their internalization and disposal. Critical insights into these events were gained recently through the development of new in vitro and in vivo models, along with advances in live-cell and intravital microscopy. This review addresses the classes of "find-me" and "eat-me" signals presented by necrotic cells and their cognate receptors in phagocytes, which in most cases differ from the extensively characterized counterparts in apoptotic cell engulfment. The roles of damage-associated molecular patterns, chemokines, lipid mediators, and complement components in recruiting and activating phagocytes are reviewed. Lastly, the physiological importance of necrotic cell removal is emphasized, highlighting the key role of impaired debris clearance in autoimmunity. ispartof: FRONTIERS IN IMMUNOLOGY vol:10 ispartof: location:Switzerland status: published

Several emerging lines of evidence support an anti-inflammatory role for nicotinamide and other vitamin B components. However, the mechanisms underlying their activity remain unclear. In the present study, we investigated the ability of nicotinamide to inhibit both neutrophil recruitment in IL-8-, LTB 4 - or carrageenan-induced pleurisy in mice and the rolling and adherence of neutrophils. Nicotinamide inhibited IL-8-, LTB 4 - and carrageenan-induced neutrophil migration, KC production and carrageenan-induced neutrophil rolling and adherence. We propose that the effects of nicotinamide in inhibiting neutrophil recruitment in carrageenan-induced pleurisy may be due to the ability of nicotinamide to inhibit the action of IL-8 and LTB 4 , decrease KC production, and inhibit early events that regulate leukocyte migration from blood vessels into tissue.

Pretreatment using celecoxib, a cyclooxygenase (COX) 2 inhibitor, or indomethacin, a nonselective COX inhibitor, reduced lypopolyssaccharide (LPS)-induced leukocyte migration to the rat peritoneal cavity. The effect of celecoxib (12 mg/kg) or indomethacin (2 mg/kg) on neutrophil chemotaxis induced by formyl-methionyl-leucyl-phenylalanine (FMLP) in an in vitro chemotactic assay (Boyden chamber) was investigated. Celecoxib and indomethacin inhibited chemotaxis induced by FMLP (Control=26.6+/-1.45, Celecoxib=12.8+/-3.04, Indomethacin=6.26+/-2.19 cells/field). When observed under intravital microscopy, a mouse cremaster preparation was used to assess the microvasculature to further investigate which step of cell recruitment was affected by these drugs. Celecoxib and indomethacin inhibited leukocyte migration induced by 0.05 microg/kg LPS injected into the cremaster muscle. However, the effect of celecoxib was associated with reduced cell rolling and adhesion, whereas indomethacin was only effective at inhibiting cell adhesion. Furthermore, SC560 pretreatment (a COX-1 selective inhibitor) of normal or LPS-challenged tissues did not alter leukocyte migration or cell adhesion, but it did enhance leukocyte rolling activity in both cases. Taken together, these results indicate that: 1) COX-1 activity is mainly related to leukocyte traffic under physiological conditions, and 2) COX-2 activity is mainly related to cell traffic under inflammatory conditions in vascular beds, suggesting a possible effect of selective COX-2 inhibitors on the expression of adhesion molecules.