Pristane-Induced Granulocyte Recruitment Promotes Phenotypic Conversion of Macrophages and Protects against Diffuse Pulmonary Hemorrhage in Mac-1 Deficiency

Abstract

Diffuse pulmonary hemorrhage (DPH) is an uncommon but critical complication of systemic lupus erythematosus. Peritoneal administration of 2,6,10,14-tetramethylpentadecane (pristane) can recapitulate a lupus-like syndrome in mice, which can develop into DPH within a few weeks, especially in C57BL/6 mice. Mac-1 (CD11b/CD18), a leukocyte adhesion molecule, is known to play a role in inflammation by regulating migration of leukocytes into injured tissue. In this study, we aimed to clarify the role of Mac-1 in pristane-induced DPH, using Mac-1−/− and wild-type (WT) mice on a C57BL/6 background. After pristane injection, Mac-1−/− mice showed reduced prevalence of DPH and attenuated peritonitis compared with WT mice. Analysis of the peritoneal lavage on days 5 and 10 after pristane treatment revealed increased numbers of eosinophils and alternatively activated macrophages, but decreased numbers of neutrophils and classically activated macrophages in Mac-1−/− mice compared with WT. Enhanced production of IL-4 and IL-13, both key mediators of macrophage polarization toward the mannose receptor+ (MMR+) phenotype, was observed in the peritoneal cavity of Mac-1−/− mice. Depletion of neutrophils and eosinophils or adoptive transfer of classically activated macrophages resulted in the exacerbation of pristane-mediated DPH in both WT and Mac-1−/− mice. Moreover, peritoneal transfer of F4/80highMMR+ alternatively activated macrophages successfully reduced the prevalence of DPH in WT mice. Collectively, Mac-1 promoted acute inflammatory responses in the peritoneal cavity and the lungs by downregulating granulocyte migration and subsequent phenotypic conversion of macrophages in a pristane-induced systemic lupus erythematosus model.

High-dimensional analysis reveals a pathogenic role of inflammatory monocytes in experimental diffuse alveolar hemorrhage

“…Whether monocytes express a receptor for IgM is controversial (54,55). Interestingly, deficiency of either CD11b or CD18 is protective in pristane-in-duced DAH (15,20). Although these complement receptors are abundantly expressed by monocytes, interpretation of previous findings is confounded by their dual function as integrins crucial for the migration and function of many cell types.…”

Neutrophils Regulate Humoral Autoimmunity by Restricting Interferon-γ Production via the Generation of Reactive Oxygen Species

“…In another inducible lupus model, neutrophils infiltrate the peritoneal cavity in response to pristane, hydrocarbon oil capable of inciting chronic inflammation and autoimmunity (Lee et al, 2011). Interestingly, depletion of neutrophils significantly ameliorated diffuse pulmonary hemorrhage in these mice (Shi et al, 2014). Of note, we did not detect neutrophil activation or death in response to amyloid upon examination of both human and mouse neutrophils, nor observed NET formation in vitro or in vivo (not shown).…”

Apoptosis inhibitor of macrophage ameliorates fungus-induced peritoneal injury model in mice

“…Preparation of M1- and M2a-like macrophages was performed according to previously established methods 58 . Briefly, bone marrow cells were harvested from the femur and tibia of AIM +/+ and AIM −/− mice, injected into ice-cold RPMI 1640 medium (Sigma-Aldrich), and filtered through a 70-μm nylon mesh.…”