LysM-domain containing (LysMD) proteins are widespread in nature and associated with host-pathogen interactions, often-binding peptidoglycan and chitin. However, the functions of mammalian LysMD proteins have not been fully defined. Chitin, a major component of fungal cell walls, has been associated with allergic disorders such as asthma. However, chitin recognition by mammals remains enigmatic at best. The principal receptor(s) on epithelial cells for chitin recognition remain to be determined. In this study, we demonstrate that LYSMD3 is expressed on the surface of human airway epithelial cells. Interestingly, LYSMD3 is able to bind chitin and β-glucan as well as fungal spores. Knockdown and knockout of LYSMD3 markedly impaired chitin and fungi-induced inflammatory cytokine production in lung epithelial cells. Antagonization of LYSMD3 ectodomain by soluble LYSMD3 protein, multiple ligands, or antibody against LYSMD3 all significantly blocked chitin signaling. Taken together our study identifies LYSMD3 as a mammalian pattern recognition receptor (PRR) for chitin and is required for the epithelial inflammatory response to chitin and fungal spores. / Doctor of Philosophy / Chitin is the main ingredient in the crustacean shells (e.g. crab, shrimp, lobster). It can also be found in fungal cell walls and insect exoskeletons like house dust mites and cockroaches. Many people are allergic to seafood, fungal spores, house dust mites, and cockroach. These allergies are thought to be driven at least partially by a response to chitin. However, how mammals sense and response to chitin is largely unknown. In plants, LysM-domain (LysMD, chitin binding domain) containing receptors are the primary receptors for chitin. These receptors can bind directly to chitin and/or mediate the innate immune response against chitin-containing pathogens such as fungi. Mammals also have LysMD containing proteins, but the functions of these proteins are unclear. In this study, we demonstrate that human LYSMD3 is a novel receptor for chitin. LYSMD3 is essential for chitin recognition and chitin induced inflammatory responses by airway epithelial cells. Our characterization of LYSMD3 as the elusive human epithelial cell receptor for chitin, resolves a long-standing mystery and provides a new insight into the context of innate immunity in mammals against chitin-containing organisms and allergic inflammation.