AMPK Metabolism in the B Lineage Modulates Humoral Responses

Abstract

A large and growing body of evidence supports functions of enzymes that regulate or effect cellular metabolism in governing the development, survival, and effector functions of immune cells—especially T cells, macrophages, and dendritic cells. Among these proteins, adenosine monophosphate-activated protein kinase (AMPK) is a conserved ATP and nutrient sensor that regulates multiple metabolic pathways to promote energy homeostasis. Although AMPK had been shown to regulate aspects of CD4 + and CD8 + T cell biology, its function in B lymphocytes has been less clear. Here, we review recent advances in our understanding of the role of AMPK in the metabolism, function, and maintenance of the B lineage.

Supplying the trip to antibody production—nutrients, signaling, and the programming of cellular metabolism in the mature B lineage

“…Moreover, mTORC1 activity was increased in AMPK-deficient B cells analyzed directly ex vivo [ 96 ]. Among intriguing findings, AMPK has consistently appeared to be dispensable for the induction of B cell activation markers as well as for the formation of steady-state B cell populations in primary GCs ([ 96 , 147 , 148 ]; reviewed in [ 149 ]). Although p-AMPKα1 T172 expression increases with activation [ 148 ], anabolic pathways presumably dominate B cell metabolism during activation and proliferation.…”

“…These findings raise unanswered but intriguing questions relating to quantitative features of the impact of increased mTORC1 on GCs and their outputs. Hyperactivation of mTORC1, by either loss of AMPK or loss of tuberous sclerosis complex 1 (TSC1) protein, did not affect GC formation ([ 91 , 96 , 148 , 165 ]; reviewed in [ 149 ]). Alternatively, hyperactivation of mTORC1 signaling by TSC1 elimination or by a constitutively active mutant of RagA (a GTPase that participates in mTORC1 activation) caused GC B cell retention in the dark zone (DZ) and impaired affinity maturation [ 136 ].…”

“…It may be that barcoding approaches will be needed to tease out how much given phenotypic subsets of GC B cells derive from a single precursor of set BCR affinity. In addition, the difficulties in quantitating exact degrees of increases or decreases in the activity and localization of mTOR complexes pose a major challenge to resolution of differences among papers on the relationship between mTORC1 and GCs or their outputs (reviewed in [ 149 ] and, for T cells [ 196 ]). Limiting dilution analyses to approximate the fate potential for single naive B cells have underscored that there is a range of options influenced but not rigidly determined by BCR affinity, such that many B cells can assume any of the potential fates [ 197 ].…”

The Immunometabolic Roles of Various Fatty Acids in Macrophages and Lymphocytes

“…In plasma cells, which are crucial for antibody production, glycolysis and oxidative glucose metabolism are activated in order to support increased mitochondrial capacity associated with the biosynthesis of antibodies [105,106]. In addition to their high mitochondrial mass, plasma cells exhibit increased autophagy: AMPK, a regulator of autophagy, is essential to generate long-term memory B cells [107,108].…”

Altered Germinal-Center Metabolism in B Cells in Autoimmunity

“…The enzyme 5' AMP-activated protein kinase (AMPK) plays a role in cellular energy homeostasis, mainly to increase glucose and fatty acid uptake and oxidation when cellular energy is low [85]. AMPK is activated in response to energy stress when it detects an increase in AMP.…”