Early macrophage influx to sites of cutaneous granuloma formation is dependent on MIP-1alpha /beta released from neutrophils recruited by mast cell-derived TNFalpha.

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