Early macrophage influx to sites of cutaneous granuloma formation is dependent on MIP-1α/β released from neutrophils recruited by mast cell–derived TNFα

Abstract

Macrophages (MΦ) play a crucial role in the development of cutaneous granulomas (CGs) initiated by foreign bodies or invasive microorganisms. However, little is known about how MΦ are recruited to sites of CG formation. To test whether mast cells (MCs) contribute to early MΦ recruitment to developing granulomas, CGs were induced in MC-deficient Kit^W/Kit^W-v mice by injection of polyacrylamide gel (PAG).Kit^W/Kit^W-v mice as well as mice deficient in the MC product TNFα exhibited markedly reduced MΦ numbers in CGs. MΦ recruitment was restored inKit^W/Kit^W-v mice reconstituted with MCs from Kit ^+/+ or TNFα^+/+, but not from TNFα^−/− mice. MC-TNFα–dependent MΦ influx required prior recruitment of MIP-1α/β–producing neutrophils (PMNs), as PMN depletion before induction of CGs completely inhibited MΦ influx, which was restored after reconstitution with PMN supernatants. These findings indicate that MΦ recruitment to cutaneous PAG- induced granulomas is the result of a sequence of inflammatory processes initiated by MC-derived TNFα followed by PMN influx and MIP-1a/β release.