Neutrophils have long been viewed as short-lived cells crucial for the elimination of extracellular pathogens, possessing a limited role in the orchestration of the immune response. This dogma has been challenged by recent lines of evidence demonstrating the expression of an increasing number of cytokines and effector molecules by neutrophils. Moreover, in analogy with their "big brother" macrophages, neutrophils integrate the environmental signals and can be polarized towards an antitumoural or protumoural phenotype. Neutrophils are a major source of humoral fluid phase pattern recognition molecules and thus contribute to the humoral arm of innate immunity. Neutrophils cross talk and shape the maturation and effector functions of other leukocytes in a direct or indirect manner, through cell-cell contact or cytokine production, respectively. Therefore, neutrophils are integrated in the activation and regulation of the innate and adaptive immune system and play an important role in the resolution or exacerbation of diverse pathologies, including infections, chronic inflammation, autoimmunity and cancer.

The development of multiple myeloma (MM) bone disease is mediated by increased number and activity of osteoclasts (OCs). Using an in vitro osteoclastogenesis model consisting of unstimulated and unfractionated peripheral blood mononuclear cells (PBMCs) from patients with MM, we showed that T cells support the formation of OCs with longer survival. Different from T-cell–depleted MM PBMC cultures, exogenous macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) were necessary for the formation of OCs; however, they did not exhibit longer survival. We found up-regulated production of RANKL, osteoprotegerin (OPG), and TNF-related apoptosis-inducing ligand (TRAIL) by fresh MM T cells. Despite high OPG levels, the persistence of osteoclastogenesis can be related to the formation of the OPG/TRAIL complex demonstrated by immunoprecipitation experiments and the addition of anti-TRAIL antibody which decreases OC formation. OCs overexpressed TRAIL decoy receptor DcR2 in the presence of MM T cells and death receptor DR4 in T-cell–depleted cultures. In addition, increased Bcl-2/Bax (B-cell lymphoma-2/Bcl2-associated protein X) ratio, following Bcl-2 up-regulation, was detected in OCs generated in the presence of T cells. Our results highlight that MM T cells support OC formation and survival, possibly involving OPG/TRAIL interaction and unbalanced OC expression of TRAIL death and decoy receptors.

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