Abstract
Activated macrophages have a greater ability of phagocytosis against pathogens that is mediated by large-scale actin rearrangement. However, molecular machineries that conduct this task have not been fully identified. Here, we demonstrate an unanticipated role of TAGLN2, a 22-kDa actin-binding protein, in Toll-like receptor (TLR)-stimulated phagocytosis. TAGLN2 was greatly induced in macrophages in response to lipopolysaccharide (LPS), a ligand for TLR4, partly via the NF-κB pathway. TAGLN2-deficient macrophages (TAGLN2−/−) showed defective phagocytic functions of IgM- and IgG-coated sheep red blood cells as well as bacteria. Cell signaling pathways involved in actin rearrangement—PI3 kinase/AKT and Ras-ERK—were also down-regulated in LPS-stimulated TAGLN2-deficient macrophages. Moreover, TAGLN2−/− mice showed higher mortality after bacterial infection than wild-type littermates. Thus, our results revealed a novel function of TAGLN2 as a molecular armament required for host defense.
Highlights
Transgelin (TAGLN), a 22-kDa actin-binding protein, was first discovered in chicken gizzard smooth muscle (SM22) with unknown function[9], and thereafter it was named as “transgelin” because of its transformation sensitive and rapid actin-gelling properties[10]
In contrast to the lymphoid cells, we noticed that macrophages derived from either bone marrow or peritoneum express minimum levels of TAGLN2 (Fig. 1a and Supplementary Fig. S1a and b), suggesting that it has a minimal function in resting macrophages
Macrophages treated with IFN-γ and LPS highly expressed TAGLN2 but no other TAGLN family members (Fig. 1b), suggesting a unique function of TAGLN2 after bacterial infection
Summary
TAGLN2 is over-induced in response to LPS in macrophages. Previously, we reported that TAGLN2 is highly expressed in immune-related tissues, such as thymus, spleen, and lymph nodes[21]. In addition to the LL-37, previous reports demonstrated that Salmonella invasion protein A (SipA) protein, which is one of the components of bacterially encoded type III protein secretion system (TTSS)−143, 44, extensively polymerizes G-actin in vitro and triggers large-scale membrane protrusions and ruffles at the site of Salmonella entry[43, 45] If this is true, it is striking because this suggests that both invasive pathogens and host macrophages have completely opposite purposes for phagocytosis, they use a highly similar mechanism to accomplish their goals. TAGLN2 recruited to the membrane and induced large-scale cytoskeletal rearrangements that are necessary for membrane protrusion and ruffling, and eventually phagocytic function These results strongly suggest that TAGLN2 is an important endogenic factor protecting the host from bacterial infection-related sepsis via controlling actin dynamics at the membrane ruffles. Only revealed an unexpected role for TAGLN2, and offered important insights into the complex molecular armamentarium required for normal host defense
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