The regulation of TNFα production after heat and endotoxin stimulation is dependent on Annexin-A1 and HSP70

Abstract

Febrile temperatures can induce stress responses which protect cells from damage and can reduce inflammation during infections and sepsis. However, the mechanisms behind the protective functions of heat in response to the bacterial endotoxin LPS are unclear. We have recently shown that Annexin-1 (ANXA1)-deficient macrophages exhibited higher TNFα levels after LPS stimulation. Moreover, we have previously reported that ANXA1 can function as a stress protein.Therefore in this study, we determined if ANXA1 is involved in the protective effects of heat on cytokine levels in macrophages after heat and LPS. Exposure of macrophages to 42°C for 1 h prior to LPS results in an inhibition of TNFα production, which was not evident in ANXA1 −/− macrophages. We show that this regulation involves primarily MYD88-independent pathways. ANXA1 regulates TNFα mRNA stability after heat and LPS, and this is dependent on endogenous ANXA1 expression and not exogenously secreted factors. Further mechanistic studies revealed the possible involvement of the heat shock protein HSP70 and JNK in the heat and inflammatory stress response regulated by ANXA1. This study shows that ANXA1, an immunomodulatory protein, is critical in the heat stress response induced after heat and endotoxin stimulation.

Unravelling Pathophysiology of Crystalline Nephropathy in Ceftriaxone-Associated Acute Kidney Injury: A Cellular Proteomic Approach

“…Of these proteins, annexin A1 shows evidence of serving as an important player in the heat stress response [22, 32], and thus best fits the proposed pathophysiology of ceftriaxone-associated AKI in this study. At present, there is no evidence supporting a conclusion that annexin A1 also plays a receptor role between distal tubular cell surface and Cef-Ca crystals.…”

“…The expression of annexin A1 (ANXA1 gene) in Cef-Ca-treated MDCK cells was validated by Western blot analysis because of its involvement in a predicted function of altered proliferation and wound healing, together with its characteristic of calcium binding [21] and playing roles in heat stress response [22]. Unexpectedly, annexin A1 was not detected in renal tubules by 4 of 5 antibodies used in Human Protein Atlas (www.proteinatlas.org/­ENSG00000135046-ANXA1/tissue).…”

Annexins – insights from knockout mice

“…Strikingly, and supporting earlier in vivo studies with recombinant AnxA1 tools (Perretti and Dalli, 2009;Sugimoto et al, 2016), AnxA1 -/-mice displayed a boosted immune response. This was characterized by an increased leucocyte migratory behavior and Croxtall et al, 2003;Hannon et al, 2003;Damazo et al, 2011;Drechsler et al, 2015reviewed in D'Acquisto et al, 2008Perretti and D'Acquisto, 2009;Perretti and Dalli, 2009;Gavins and Hickey, 2012;Yang et al, 2013a;Sugimoto et al, 2016Nair et al, 2015Yang et al 2013breviewed in D'Acquisto et al, 2008Perretti and D'Acquisto, 2009;Perretti and Dalli, 2009;Gavins and Hickey, 2012;Yang et al, 2013a;Sugimoto et al, 2016 Wound (Hannon et al, 2003). Altogether, this prominent extracellular AnxA1 activity suggested the existence of an AnxA1 receptor.…”

“…This indicates that compromised secretion upon AnxA1 deletion may also occur and contribute to other disease models investigated in the AnxA1 KO strain. In addition, an impact of AnxA1 on transcriptional activation, mRNA transport and stability has also been described (Bist et al, 2013;Nair et al, 2015). It is tempting to speculate that yet unknown AnxA1-dependent protein-protein or protein-lipid interactions that are lacking in the AnxA1 KO strain add to altered membrane trafficking in the secretory pathway.…”

“…Interestingly, several consequences of AnxA1 deficiency inside cells might even potentiate the extracellular anti-inflammatory mode of AnxA1 action. On the one hand, altered activity of multiple signaling pathways in AnxA1 -/-macrophages contribute to increased production of inflammatory cytokines, such as interferon-β and tumor necrosis factor α (Bist et al, 2013;Nair et al, 2015). On the other hand, the secretome of mesenchymal stromal cells from the AnxA1 KO mice lacks the ability to stimulate glucose-induced insulin secretion of pancreatic β cells (Rackham et al, 2016).…”