Abstract
p38MAP kinase (MAPK) signal transduction pathways are important regulators of inflammation and the immune response; their involvement in immune cell development and function is still largely unknown. Here we analysed the role of the p38 MAPK isoforms p38γ and p38δ in B cell differentiation in bone marrow (BM) and spleen, using mice lacking p38γ and p38δ, or conditional knockout mice that lack both p38γ and p38δ specifically in the B cell compartment. We found that the B cell differentiation programme in the BM was not affected in p38γ/δ-deficient mice. Moreover, these mice had reduced numbers of peripheral B cells as well as altered marginal zone B cell differentiation in the spleen. Expression of co-stimulatory proteins and activation markers in p38γ/δ-deficient B cells are diminished in response to B cell receptor (BCR) and CD40 stimulation; p38γ and p38δ were necessary for B cell proliferation induced by BCR and CD40 but not by TLR4 signaling. Furthermore, p38γ/δ-null mice produced significantly lower antibody responses to T-dependent antigens. Our results identify unreported functions for p38γ and p38δ in B cells and in the T-dependent humoral response; and show that the combined activity of these kinases is needed for peripheral B cell differentiation and function.
Highlights
B cell development from pluripotent haematopoietic stem cell to immature B cells in the bone marrow (BM), or from immature to mature B lymphocytes in the periphery, is regulated by multiple signalling pathways (Reth and Brummer, 2004)
We examined the implication of p38γ and p38δ in B cell development comparing different B cell subpopulations by cytometry in the bone marrow (BM) of wild type (WT) mice, p38γ and p38δ deficient (p38γ/δ−/−) and B cell p38γ and p38δ deficient (CD19-CreKI/+-p38γ/δf/f)
The absolute cell numbers in BM were similar in p38γ/δ−/− and WT mice, and in CD19-CreKI/+-p38γ/δf/f and p38γ/δf/f mice (Figure 1A). p38γ/δ−/− lymphocytes differentiated into pro-B, p38γ/δ in B Cell p38γ/δ in B Cell pre-B, immature and mature B cells in the BM (Figures 1B–D)
Summary
B cell development from pluripotent haematopoietic stem cell to immature B cells in the bone marrow (BM), or from immature to mature B lymphocytes in the periphery, is regulated by multiple signalling pathways (Reth and Brummer, 2004). B cells are one of the major effectors of host defence against infections by producing antibodies that neutralise the invading pathogen All these processes are mainly controlled by the stimulation of B-cell receptor (BCR), CD40 and/or chemokine and cytokine receptors. The mammalian p38MAPK family is composed of four members (p38α, p38β, p38γ, and p38δ) encoded by distinct genes; they are broadly expressed and activated by a wide range of cellular stresses and in response to inflammatory cytokines These kinases share highly similar protein sequences and all are activated by phosphorylation mediated primarily by MAPK kinases (MKK) and MKK6 (Remy et al, 2010); they differ in their expression patterns, substrate specificities and sensitivities to chemical inhibitors, and represent related, but clearly distinct p38MAPK subgroups (p38α/p38β and p38γ/p38δ) (Cuenda et al, 1997; Cuenda and Rousseau, 2007; Cuenda and Sanz-Ezquerro, 2017). These kinases share highly similar protein sequences and all are activated by phosphorylation mediated primarily by MAPK kinases (MKK) and MKK6 (Remy et al, 2010); they differ in their expression patterns, substrate specificities and sensitivities to chemical inhibitors, and represent related, but clearly distinct p38MAPK subgroups (p38α/p38β and p38γ/p38δ) (Cuenda et al, 1997; Cuenda and Rousseau, 2007; Cuenda and Sanz-Ezquerro, 2017). p38α, the most abundant and best-characterised p38MAPK isoform, is activated during both innate and adaptive immune responses, and is a key regulator of the immune response (Gaestel et al, 2009; Rincon and Davis, 2009); evidence is, emerging that implicates p38γ and p38δ in this process (Cuenda and Sanz-Ezquerro, 2017)
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