Pristane-induced granulocyte recruitment promotes phenotypic conversion of macrophages and protects against diffuse pulmonary hemorrhage in Mac-1 deficiency

• Published in: The Journal of immunology (1950) Vol. 193; no. 10; pp. 5129 - 5139
• Main Authors: Shi, Yiqin, Tsuboi, Naotake, Furuhashi, Kazuhiro, Du, Qiuna, Horinouchi, Asuka, Maeda, Kayaho, Kosugi, Tomoki, Matsuo, Seiichi, Maruyama, Shoichi
• Format: Journal Article
• Language: English
• Published: United States 15.11.2014
• Subjects: Animals; Antigens, Differentiation - genetics; Antigens, Differentiation - immunology; Cell Movement; Gene Deletion; Gene Expression Regulation; Granulocytes - cytology; Granulocytes - immunology; Hemorrhage - chemically induced; Hemorrhage - genetics; Hemorrhage - immunology; Hemorrhage - pathology; Interleukin-13 - genetics; Interleukin-13 - immunology; Interleukin-4 - genetics; Interleukin-4 - immunology; Lung - immunology; Lung - pathology; Lupus Erythematosus, Systemic - chemically induced; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Macrophage-1 Antigen - genetics; Macrophage-1 Antigen - immunology; Macrophages - immunology; Macrophages - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Peritoneal Cavity - pathology; Peritoneal Lavage; Phenotype; Severity of Illness Index; Signal Transduction; Terpenes
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1401051

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 F4/80(high)MMR(+) 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.