Receptor crosstalk: reprogramming B cell receptor signalling to an alternate pathway results in expression and secretion of the autoimmunity-associated cytokine, osteopontin

Abstract

Receptor crosstalk: reprogramming B cell receptor signalling to an alternate pathway results in expression and secretion of the autoimmunity-associated cytokine, osteopontin (Review). J Intern Med 2009; 265: 632-643.Intracellular signalling emanating from the B-cell antigen receptor is considered to follow a discrete course that requires participation by a set of mediators, grouped together as the signalosome, in order for downstream events to occur. Recent work indicates that this paradigm is true only for naïve B cells. Following engagement of the IL-4 receptor, a new, alternate pathway for B-cell receptor (BCR)-triggered intracellular signalling is established that bypasses the need for signalosome elements and operates in parallel with the classical, signalosome-dependent pathway. Reliance on Lyn and sensitivity to rottlerin by the former, but not the latter, distinguishes these two pathways. The advent of alternate pathway signalling leads to production and secretion by B cells of osteopontin (Opn). As Opn is a polyclonal B-cell activator that is strongly associated with a number of autoimmune diseases including lupus and rheumatoid arthritis, this novel finding is likely to be clinically relevant. Our results highlight the potential role of B-cell-derived Opn in immunity and autoimmunity and suggest that stress-related IL-4 expression might act to strengthen immunoglobulin secretion at the risk of autoantibody formation. Further, these results illustrate receptor crosstalk in the form of reprogramming, whereby engagement of one receptor (IL-4R) produces an effect that persists after the original ligand (IL-4) is removed and results in alteration of the pathway, and outcome, of signalling via a second receptor (BCR) following its activation.

Fig. 1

IL-4 induces an alternate pathway for BCR signalling. Some elements involved in mediating BCR-triggered intracellular signalling are shown. Mediators grouped together as the signalosome (PI-3K, Btk, BLNK, PLCγ2, and PKCβ) are indicated by the shaded region. B cell treatment with IL-4 produces an alternate pathway for BCR signalling, shown as a green arrow, that bypasses the need for multiple signalosome elements to bring about the downstream event of ERK phosphorylation, which is dependent on MEK activation here as in the classical pathway for BCR signalling. However, IL-4 treatment does not alter the requirement of signalosome mediators for BCR-triggered NF-κB activation. IL-4 induction of the alternate pathway for BCR signalling to pERK requires time and protein synthesis.

Fig. 2

The IL-4-induced alternate pathway operates in parallel with the classical pathway, is blocked by rottlerin, and depends on Lyn. Several key elements of the classical (black arrows) and alternate (green arrows) BCR signalling pathways are shown. Naïve B cells contain only one signalling pathway that is entirely dependent on signalosome elements such as PI-3K or PKCβ. IL-4 treatment produces a new, alternate pathway for BCR signalling that operates in parallel alongside, but does not replace, the classical pathway. The alternate pathway does not utilize signalosome elements but, in contrast to the classical pathway, requires Lyn and a rottlerin-inhibitable factor. Complete interruption of BCR-triggered ERK phosphorylation in IL-4-treated B cells requires separate inhibition of both the classical and the alternate pathways with, for example, the combination of LY294002 plus rottlerin.

Fig. 3

Osteopontin expression is a specific outcome of alternate pathway signalling. BCR triggering induces Opn expression and secretion in IL-4-treated B cells that signal via both the classical and alternate pathways, but not in naïve B cells, that only signal via the classical pathway. Inhibitor studies using LY294002 and rottlerin indicate that Opn expression results from the coordinate action of both pathways rather than the alternate pathway alone.