Ampk regulates IgD expression but not energy stress with B cell activation

Abstract

Ampk is an energy gatekeeper that responds to decreases in ATP by inhibiting energy-consuming anabolic processes and promoting energy-generating catabolic processes. Recently, we showed that Lkb1, an understudied kinase in B lymphocytes and a major upstream kinase for Ampk, had critical and unexpected roles in activating naïve B cells and in germinal center formation. Therefore, we examined whether Lkb1 activities during B cell activation depend on Ampk and report surprising Ampk activation with in vitro B cell stimulation in the absence of energy stress, coupled to rapid biomass accumulation. Despite Ampk activation and a controlling role for Lkb1 in B cell activation, Ampk knockout did not significantly affect B cell activation, differentiation, nutrient dynamics, gene expression, or humoral immune responses. Instead, Ampk loss specifically repressed the transcriptional expression of IgD and its regulator, Zfp318 . Results also reveal that early activation of Ampk by phenformin treatment impairs germinal center formation but does not significantly alter antibody responses. Combined, the data show an unexpectedly specific role for Ampk in the regulation of IgD expression during B cell activation.

Mitochondrial function is essential for humoral immunity by controlling flux of the TCA cycle, phosphatidic acid and mTOR activity in B cells

“…These data are in accordance with original proposals linking the TCA, AMPK and MTOR (Tokunaga et al, 2004) and can indirectly also explain the effects on CSR and the GC reaction, both of which are controlled by MTOR and sustained proliferation (Chiu et al, 2019;Ersching et al, 2017;Keating et al, 2013;MacLennan, 1994;Stavnezer et al, 2008;Zhang et al, 2013). In line, AMPK has previously been shown to control the GC reaction (Lee et al, 2017;Waters et al, 2019). Our data are also consistent with DNTmediated activation of AMPK in primary cultured chondrocytes (Holzer et al, 2019).…”

The role of metabolic checkpoint regulators in B cell survival and transformation

“…However, AMPKα1 ablation does not affect B cell proliferation, nutrient uptake, or GC formation suggesting that other LKB1 targets play a more prominent role in GC B cells. 21 Lastly, a typical adaptive response to low oxygen levels is the stabilization of the transcription factor hypoxia-inducible factor 1α (Hif1α) and a metabolic shift toward glycolysis. 69 Consistent with the GC being a hypoxic environment, GC B cells have been found to accumulate Hif1α.…”

“…Intriguingly, not all B cell subsets require LBK1/AMPK activity for their survival or proliferation. While a disruption of AMPK signaling results in increased apoptosis of developing B cells, mature stimulated B cells are capable of proliferation in the absence of LBK1 or AMPK activity . This suggests that these metabolic regulators are not essential for B cell proliferation in general.…”

“…Furthermore, mice deficient for the AMPK activator LKB1 show an accumulation of transitional B cells and reduction of mature B cells (Figure 2). However, unlike LKB1‐deficient B cells AMPK‐deficient B cells do not show a maturation/survival defect suggesting that AMPK plays a redundant role in mature B cells …”

“…Among other targets, LKB1 regulates B cell metabolism by activating AMPK. However, AMPKα1 ablation does not affect B cell proliferation, nutrient uptake, or GC formation suggesting that other LKB1 targets play a more prominent role in GC B cells …”