Integrins, mast cells, and innate immunity

Over the past several years, there has been increasing awareness of the importance of mast cells in initial host defense against invading bacteria.¹  In several different models of infection of normally sterile body cavities, mast cells have a significant role in initiating the process of innate immunity, especially in the chemoattraction of professional phagocytes, particularly polymorphonuclear neutrophils (PMNs), to the site of infection. Early influx of PMNs can be critical for control of infection. This essential early role for mast cells results from their unique property of synthesizing tumor necrosis factor α (TNFα) constitutively, so that it can be released rapidly in response to an appropriate secretion signal. Mast cell–derived TNFα is a major chemoattractant during early PMN recruitment, as is mast cell–derived LTB4, which is made in response to interaction with bacteria. While mechanisms of mast cell secretion in response to crosslinking immunoglobulin E (IgE) receptors and secretagogues have been studied extensively, not much is known about how bacteria and bacterial products activate secretion of the mast cell mediators of host defense. Now, in this issue of Blood, Edelson and colleagues (page 2214) have shown that mast cell expression of the integrin α2β1, a receptor for extracellular matrix collagens and for at least one cell-surface molecule, E-cadherin, is required for PMN influx and interleukin-6 (IL-6) accumulation induced by intraperitoneal infection with the gram-positive bacterium Listeria monocytogenes. Although an important role for α2β1 on monocytes and inflammatory T cells in the process of migration to sites of inflammation had been established,²  the high level of expression of α2β1 on mast cells and its requirement in innate immune responses were not previously appreciated. The mast cell defect in α2β1 deficiency appears to be one of cell activation rather than of development, because peritoneal mast cell number, size, and granularity are comparable in wild-type and α2β1^–/– mice, and the nonspecific secretagogue compound 48/80 causes degranulation identically in mast cells from the 2 strains. As with all good experiments, the findings published in this paper suggest several new, important problems for understanding how mast cells contribute to host defense. The mast cell receptors for Listeria and zymosan, a derivative of the fungal cell wall that also induces PMN influx into the peritoneum in an α2β1-dependent fashion, are not known. The relevant ligand for the α2β1 integrin likewise is not clear. There is precedent for the possibility of synergy between integrin ligation and other signaling receptors in both the anchorage dependence of growth of many cell types³  and the adhesion-dependent activation of PMNs in response to inflammatory stimuli,⁴  but no understanding of whether and how crosstalk between bacterial and matrix protein signals might work in mast cells. Finally, Edelson et al show that early dissemination of Listeria infection is enhanced by the absence of α2β1 integrin but not of mast cells. This clearly demonstrates that α2β1 function on a cell type in addition to the mast cell is important in early control of infection. There are more surprises yet to come as the role for this integrin in innate immunity and host defense is discovered.