The Four-and-a-Half LIM Domain Protein 2 Supports Influenza A Virus–Induced Lung Inflammation by Restricting the Host Adaptive Immune Response

Abstract

Four-and-a-half LIM domain protein 2 (FHL2) is a multifunctional adaptor protein with fine-tuning adjustment properties. It acts as a regulator of signaling cascades but also as a cofactor of transcription and controls several anti-inflammatory immune responses. Recently, we described FHL2 as a novel regulator of influenza A virus propagation. We have shown that in vitro FHL2 restricts viral replication by accelerating the interferon regulatory factor 3-dependent transcription of the Ifnb1 gene. In this work, we unraveled an ambiguous role of FHL2 during influenza A virus infection in vivo. Although FHL2 restrained viral replication during the first 24 hours of infection, it significantly delayed viral clearance afterward. Comparison of lung immune status of wild-type and FHL2 knockout mice during influenza virus infection did not acknowledge significant differences in the innate host immune response but revealed an improved migration of dendritic cells from infected lungs into draining lymph nodes as well as increased levels of activated CD8 T lymphocytes accumulated in the lungs of FHL2 knockout mice.

The role of FHL2 in wound healing and inflammation

“…Here, myofibroblasts display the highest expression (9,26). A similar expression kinetic of FHL2 is also shown during regeneration of other tissues, like recovery of mouse ischemic muscles or lungs after infection with sublethal doses of influenza viruses (27,28). Lung infection results in massive tissue damage due to the apoptosis of infected cells (28).…”

“…A similar expression kinetic of FHL2 is also shown during regeneration of other tissues, like recovery of mouse ischemic muscles or lungs after infection with sublethal doses of influenza viruses (27,28). Lung infection results in massive tissue damage due to the apoptosis of infected cells (28). The amount of FHL2 in the lungs increases with growing inflammation and decreases slowly after clearance of the viral infection and ongoing restoration of damaged tissue (unpublished results).…”

“…Infection of FHL2-KO mice with the influenza viruses also revealed a decrease in attraction of neutrophils and peripheral macrophages, but not NK cells, into inflamed lungs (28). In contrast, infiltration of influenza-infected FHL2-KO lungs by cytotoxic CD8 + IFN-g + T lymphocytes was increased compared with WT lungs.…”

“…Furthermore, induction of the cellular innate immune response to pathogens leads to rapid synthesis of type I IFN and other proinflammatory cytokines, additionally optimizing wound healing by inhibiting viral replication by different mechanisms, restraining their spread, and restricting tissue damage. Generally, respiratory infection by influenza viruses leads to rapid and massive damage of lung tissue due to apoptosis of infected cells, and FHL2 has been shown to counteract this process (28,48). The accumulating viral RNA is sensed by the intracellular retinoic acid-inducible gene I receptor, which in turn leads to activation of NF-kB, activating transcription factor/jun, and IFN regulatory factor 3 (IRF3) transcription factors, resulting in the induction of type I IFN molecules only a few hours after infection (47).…”

“…Cells lacking FHL2 are deficient in this property. Consequently, FHL2-KO cells produced over 10 times more viral progeny than wild-type (WT) cells, and as a result, the lungs of FHL2-KO mice were exposed to a more severe influenza virus-mediated tissue damage at early stages of infection than WT mice (28,48). The defect of FHL2-KO cells in the IFN-b response could easily be restored by the expression of recombinant FHL2, which also reduced virus replication (48).…”