Howard R. Katz
Brigham and Women's Hospital
Rheum., Imm., & Allergy, Smith Bldg., Rm. 638A
1 Jimmy Fund Way
Boston, MA 02115
The long-term focus of the Katz lab has been the Leukocyte Immunoglobulin-like Receptor (LILR) family of inhibitory and activating cell-surface receptors. We defined the first member of this family, now termed LILRB4, as a receptor on mast cells that has two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic domain. We then established that LILRB4 inhibits IgE-mediated activation of mast cells in vitro, defined the signal transduction pathway by which LILRB4 inhibits activation, and identified the integrin alpha(v) beta(3) as a ligand for LILRB4. We also created LILRB4 knockout mice and established that LILRB4 is an endogenous inhibitor of mast cell activation and immediate hypersensitivity (anaphylactic) reactions. LILRB4 is also expressed on neutrophils and is rapidly upregulated in response to activating stimuli such as lipopolysaccharide (LPS), suggesting that LILRB4 provides a negative feedback loop for innate immune responses. Indeed, we found that LILRB4 downregulates LPS-induced, neutrophil-dependent thrombohemorrhagic reactions and inflammatory arthritis. We have also found that LILRB4 is expressed on dendritic cells (DCs) and is rapidly upregulated when lung DCs ingest inhaled antigen, which provided another example of LILRB4 as an early feedback signal. Accordingly, LILRB4 inhibits the migration of antigen-bearing lung DCs to the draining lymph nodes (LNs) when the lung is sensitized for an allergic response. This results in less recruitment of antigen-specific T cells to the LNs and reduced pulmonary inflammation. The studies established that LILRB4 provides a rapid negative regulatory response to cells of the innate immune system that attenuates various forms of pathologic inflammation. Current studies are focused on the mechanisms by which LILRB4 inhibits DC functions, regulation of additional models of immune and inflammatory pathology by LILRB4, and functions of the human analogs of LILRB4 and its related family of receptors. We predict that these receptors will provide new therapeutic targets for control of inflammatory diseases.
M. C. Castells, L. B. Klickstein, K. Hassani, Cumplido J.A., M. E. Lacouture, K. F. Austen, and H. R. Katz. gp49B1-alpha(v) beta(3) interaction inhibits antigen-induced mast cell activation. Nature Immunol. 2:436-442, 2001.
M. Daheshia, D. S. Friend, M. J. Grusby, K. F. Austen, and H. R. Katz. Increased severity of local and systemic anaphylactic reactions in gp49B1-deficient mice. J.Exp.Med. 194:227-233, 2001.
J. S. Zhou, D. S. Friend, A. F. Feldweg, M. Daheshia, L. Li, K. F. Austen, and H. R. Katz. Prevention of lipopolysaccharide-induced microangiopathy by gp49B1: Evidence for an important role for gp49B1 expression on neutrophils. J.Exp.Med. 198:1243-1251, 2003.
J. S. Zhou, W. Xing, D. S. Friend, K. F. Austen, and H. R. Katz. Mast cell deficiency in KitW-sh mice does not impair antibody-mediated arthritis. J.Exp.Med. 204 (12):2797-2802, 2007.
R. G. Breslow, J. J. Rao, W. Xing, D. I. Hong, N. A. Barrett, and H. R. Katz. Inhibition of Th2 adaptive immune responses and pulmonary inflammation by leukocyte Ig-like receptor B4 on dendritic cells. J.Immunol. 184:1003-1013, 2010.
Last Update: 1/6/2014