The many faces of Mac‐1 in autoimmune disease

Abstract

Mac-1 (CD11b/CD18) is a β2 integrin classically regarded as a pro-inflammatory molecule because of its ability to promote phagocyte cytotoxic functions and enhance the function of several effector molecules such as FcγR, uPAR, and CD14. Nevertheless, recent reports have revealed that Mac-1 also plays significant immunoregulatory roles, and genetic variants in ITGAM, the gene that encodes CD11b, confer risk for the autoimmune disease systemic lupus erythematosus (SLE). This has renewed interest in the physiological roles of this integrin and raised new questions on how its seemingly opposing biological functions may be regulated. Here, we provide an overview of the CD18 integrins and how their activation may be regulated as this may shed light on how the opposing roles of Mac-1 may be elicited. We then discuss studies that exemplify Mac-1's pro-inflammatory versus regulatory roles particularly in the context of IgG immune complex-mediated inflammation. This includes a detailed examination of molecular mechanisms that could explain the risk-conferring effect of rs1143679, a single nucleotide non-synonymous Mac-1 polymorphism associated with SLE.

CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus

“…14, 17-21, and reviewed in ref. 22), including increased tissue infiltration of leukocytes and immune-mediated injury in lupus-prone mice (19,20). These data further suggest that CD11b plays a protective role in SLE.…”

What people with Down Syndrome can teach us about cardiopulmonary disease

“…CD18 integrins are composed of a unique CD11 subunit noncovalently bound to CD18 (β 2 integrin, Hsa21). The role of these integrins is to support key leukocyte adhesive functions critical to antigen presentation, efferocytosis and pathogen clearance [187]. Some reports suggest that CD18 is overexpressed on Down syndrome myeloid cells [188].…”

“…However, other studies have not detected any increased CD18 on myeloid cells [189], and the differential findings may be related to whether the cells used had been transformed (lymphoblastoid cells). Due to the importance of CD18 in mediating appropriate leukocyte responses [187], the potential correlation of CD18 expression to gene dosage in Down syndrome should be examined carefully.…”

A systems approach to renal inflammation in SLE

“…ID4 regulates cell differentiation in multiple cell types and also enhances estrogen production and signaling (78); how this influences the course of LN is currently unknown. ITGAM encodes for the alpha chain of the CD11b (complement receptor 3) adhesion molecule that is expressed on myeloid cells and has both protective and pro-inflammatory functions in inflammation (79, 80). ITGAM polymorphisms are associated both with lupus susceptibility and severity and recent functional studies have determined that the dominant polymorphism R77H decreases ligand binding to CD11b under flow conditions and may compromise the inhibitory functions of the molecule by altering the affinity of the molecule for its ligands (79, 80).…”

“…ITGAM encodes for the alpha chain of the CD11b (complement receptor 3) adhesion molecule that is expressed on myeloid cells and has both protective and pro-inflammatory functions in inflammation (79, 80). ITGAM polymorphisms are associated both with lupus susceptibility and severity and recent functional studies have determined that the dominant polymorphism R77H decreases ligand binding to CD11b under flow conditions and may compromise the inhibitory functions of the molecule by altering the affinity of the molecule for its ligands (79, 80). We found that the increase in expression of CD11b in all three murine models is due both to an increase in CD11b expressing cell infiltrates and an increase in CD11b expression on renal macrophages.…”